Rett syndrome (RTT) is a complex Autism Spectrum Disorder (ASD) that is caused by mutations in the MECP2 gene and affects approximately 1 in 10,000 live female births worldwide. In addition to cognitive, motor and behavioral deficits, one of the most physically debilitating consequences of RTT is severe disruption in the control of breathing, and up to 25% of RTT patients may die prematurely of cardiorespiratory complications. Currently, there are no treatments available for breathing disorders, or any other neurologic deficits in RTT. Our understanding of neural mechanisms that underlie respiratory dysfunction in RTT is hampered by the fact that we still know little about how loss of MECP2 affects neuronal and/or synaptic function in specific brainstem respiratory circuits. Therefore, the proposed research takes a multidisciplinary approach to define how genetic loss of MECP2 disrupts respiratory control, focusing on modulation of excitatory-inhibitory balance in key respiratory reflex pathways in the brainstem using a well-defined mouse model of the disease. Electrophysiological methods will be used in brainstem slices in vitro to test the hypothesis that increased excitability at primary afferent synapses regulating reflex responses to hypoxia and lung inflation contributes to respiratory circuit dysfunction in RTT and to define underlying mechanisms. We will also examine how deficits in Brain Derived Neurotrophic Factor (BDNF), a key neuronal signaling molecule whose expression is severely decreased in RTT, contribute to synaptic dysfunction, as well as the ability of molecules that enhance BDNF signaling to restore normal function in RTT mice in vitro and in vivo. In addition, we will use Fos immunostaining to map sites throughout the brainstem respiratory network at which neuronal and/or synaptic function is disrupted in vivo. Finally, we will examine how a common polymorphism in the human BDNF gene, Val66Met-BDNF, influences the severity of respiratory symptoms and the therapeutic response to BDNF- targeted therapies in mice. The proposed research aims to define mechanisms that underlie respiratory dysfunction in RTT using innovative experimental approaches and mouse models. By focusing on synaptic excitability, and BDNF-mediated signaling in particular, it is hoped these studies will foster development of new therapeutic strategies for breathing disorders in RTT. Moreover, it is hoped that insights obtained from analysis of circuit dysfunction in RTT will be broadly applicable to ASDs as a whole.